DESCRIPTION: ProlX Pharmaceutical has demonstrated that thioredoxin has an important role in maintaining the transformed phenotype of some human cancers as well as their resistance to chemotherapeutic drugs and is thus a highly rational target for novel cancer drug development. The studies described herein, suggest that thioredoxin is a human anti apoptosis and oncogene that is overexpressed by a number of human cancers. ProlX has exclusive worldwide rights to develop the thioredoxin target and is dedicated to exploiting these observations and rapidly developing agents that selectively disrupt this novel signal transduction pathway. The objective of this Phase I proposal is to develop novel inhibitors of thioredoxin redox system based on a new pharmacophore, identified from the NCI database using ProlX lead compound activities in the 60 cell lines screen and the COMPARE analyses. The Specific Aims of the proposal are 1) to synthesis selective inhibitors of the thioredoxin system using combinatorial chemistry for lead optimization; 2) to investigate the specificity of the compounds for thioredoxin/thioredoxin reductase signaling in vitro; and 3) to evaluated the most active analogues for anti-tumor activity in vivo. These studies will provide novel lead anticancer candidates for further preclinical development, including toxicology, pharmacokinetic studies and the eventual Phase I clinical trial, which will be the subject of a future Phase II application. PROPOSED COMMERCIAL APPLICATION: One is every four deaths in the US is doe to cancer. The overall cancer drug market exceeds $2 billion in the USA. There is significant need to identify novel and selective small molecule- based cancer therapies. This proposal seeks to undertake the synthesis of a chemical library of thioether analogues as potential anticancer drugs, which through thioredoxin inhibition would provide novel therapies against breast, lung, colon and gastric cancer, all which have been found to have elevated thioredoxin levels.